Oxidation of alpha, beta-unsaturated hydroxy-steroids



United States Patent 3,118,881 @XHDATIGN @F oc,fi-UNSATURATED HYDRQXYSTERUHDS Albert Wettstein, Riehcn, and Georg Annex, Karl Heusler, and Peter Wieland, Basel, Switzerland, assignors to Qiha Corporation. a corporation of Delaware No Brewing. Filed Ian. 17, 1961, Ser. No. 83,164 (Claims priority, application dwitzerland Jan. 19, W60 4- Qlaims. ((Cl. zen-4.39.55

The present invent-ion relates to a new process for the selective oxidation of polyhyd'oxy-steroids which makes it possible to oxidize ego-unsaturated carbinols selectively to forr; and-unsaturated ketones in an extremely simple way without afiecting any other free hydroxyl groups.

The present invention is of particular importance because many naturally occurring or modified hormones of the androstane and pregnane series contain an :5- unsaturated keto grouping, viz a A -3-keto group, as well as one or more free hydroxyl groups in other positions of Lhe steroid skeleton. Among these compounds there may be mentioned, for example, testosterone, lid-by droxy-tcstosterone, l eichsteins substance E (A=-3-oxollfiIl7cZ2GI2l tetrahydroxy pregnene) and the like. Other hydroxy-steroids which contain an curl-unsaturated lreto group are important intermediates for the synthesis of physio-logically active compounds; for example A -3- oxo-ZO-hydroxy-pregnenes and their derivatives are suitable starting materials for the synthesis of 18-oxygenated steroids which can be converted into the highly active suprarenal cortex hormone, aldosterone.

This conversion is carried out by the process described in patent applications No. 7,525 of February 9, 1960, No. 7,542 of February 9, 1%0and No. 7,543 of February 9, 196* all by GSliZil leger et al. These processes consist, for example, in converting A -3-e-thylenedioxylltt-acyloxy-20-hydroxyspregnene with lead tetraacetate into the corresponding 18:20-oxido compound and, after *etal cleavage, converting the latter into A -3-keto-11sl8: 2=-triacyloxy-pregnene by treatment with an acylating and after hydrolysis into the free 11:18:20-triol. After lotion with chromic acid in glacial acetic acid there is octained the 18-20-lactone of A -3:ll-dioxo- 20-hydroxy-pregnene-18-acid which, after ketalization, can be reduced with sodium boron hydride to the 18 11- lactc-ne of A 3-ethylene-dioxy-1lfiz20-dihydroxy pregncnel8-acid. The ZG-hydroxyl group is oxidized to the keto group with pyridine-chromic acid. The conversion of this compound into aldo-sterone is carnied out in known manner by condensing with oxalic ester to the Zl-oxalo ester, iodination, treatment with potassium acetate to the 2l-acetate and "hydrolysis to form the 18- l1-lactone of 4 3:20 clilceto 11,8221 dihydroxy-pregnene-lS-aci From the latter the 2l-monoacetate of aldosterone is obtained in known manner by ketalization, reduction with lit um hydride, acetylation land ketal cleavage.

All the above mentioned hydroxylated steroid-A 6- ketenes can be easily prepared by the process of the invention from corresponding A -3-hydroxy-compounds.

Various prowsses have been described for the selective oxidation of cue-unsaturated carbinols in the presence of cull-saturated carbinol groups. In many cases, for example, this is easily carried out with the aid of active manganese dioxide. As, however, a great excess of the latter must be used, it is often impractical for industrial processes, particularly in the case or" compounds which contain more than two hydroxyl groups, these compounds adherin often very strongly to the oxidizing agent and it sometimes being impossible to detach them completely, even with large quantities of solvent. In addition, oxidation with manganese dioxide leads to considerable quantities of further dehydrogenated compounds when the reaction is longer and/or when the reaction conditions are more vigorous. In the case of A 5:20dihydroxy-pregnene, selective oxidation of the 3- hydroxyl group was also carried out with bromace-tarnide, but the yield is fairly satisfactory only under strictly controlled reaction conditions, as with this oxidizing agent bromine containing lay-products are formed in addition tothe products oxidized in the 20-positi0n; these byproducts make the isolation of the pure A -3-oxo-20- hydrox -oompound more difiicult.

Another process for the oxidation of A -3 hydroxysteroids in which other hydroxyl groups remain partially unaffected consists in boiling a A -3-hydroxy-steroid with Raney nickel in acetone. The yield of pure oxidation products, panticularly in the case of those which contain further free hydro-xyl groups, is inadequate for industrial processes and amounts, for example, to only about 50% in the oxidation of A -3: l7-dihydroxy-androstene to testosterone.

The new process for the selective oxidation of polyhy-droxy-steroids consists in treating a steroid with sev eral oxidiza'ole carbinol groups some of which contain a double bond in the cud-position, in an aromatic hydrocarbon with a carbonyl compound in the presence of a light metal alcoholate until absorption in ultraviolet light reaches a maximum between 230 and 260 m As aromatic hydrocanbons there are advantageously sed those solvents known for the Oppenauer oxidation, particularly benzene, toluene and xylene; as light metal alcoholates there are suitable more especially the tertiary butylates or isopropylates of aluminum or magnesium which are readily soluble in the mentioned solvents.

Halogenous aluminum alcoholates, such as aluminum chlorotertiary butyliate or aluminum phenolate, may also be used. As carbonyl compounds there are primarily used ketones, i.e. aliphatic, alicyclic or araliphatic ketones, suoh as acetone, methyl-ethyl-ketone, methyl-isopropylketone, cyclohcxanone, methyl-cyclohexanone, benzophenone, or quinones, such as benzoquinone, naphthoquinone or anthraquinone.

it has been found that azfl-unsaturated carbinols are oxidized much more rapidly with the above reagents than saturated carbinols so that when the maximum ultraviolet absorption due to the etzuunsaturated carbonyl compound formed is reached, the saturated carbinol groups are practically unchanged. The reaction conditions of the present process are therefore substantially milder than those normally used for the oxidation of saturated or {ivy-unsaturated carbinols. The reaction time and temperature depend essentially on the activity or" the light metal alcohol-ate and the oxidation potential of he carbonyl compound used. An industrially, extremely simple method of performing the invention consists, for example, in oxidation with aluminum tertiary butylate and acetone in benzene at 2025 C. Under these conditions the maximum ultraviolet absorption is reached in a few hours. At a higher temperature or when a carbonyl compound with a higher oxidation potential is used, the reaction time must be shorter. When catalytic quantities of anthraquinone are used as oxidizing agent and the reaction mixture is stirred under 0xygen, the course of the oxidation can also be followed by observing t e consumption of oxygen for the reoxidation of the anthrahydroquinone fopmed.

As starting materials there are used M G-unsaturated steroid-carbinols, for example A -3-, A -7-, A -20-hydroxycompounds and the like. These are readily accessible by reducing the corresponding txIfl-UDSEllllfltfid ketones with a complex light metal hydride, such as lithium aluminum hydride, sodium boron hydride, lithium boron hydride, lithium trialkoxy-aluminum hydride; simultaneous ly with the cue-unsaturated xeto group reduced saturated ketones remain as carbinol groups after the oxidation according to the present process. The combination of the reduction with the oxidation of the present process is, consequently, in effect a selective reduction of steroid polyketones. It is easily possible to convert M-androstene- 3 17-dione into testosterone and progresterone into A -20- hydroxy-pregnene-3-one by reduction and subsequent oxidation by means of the present process. Other starting materials are, for example, A -3z20-dihydroxypregnenes substituted in the ll-position by a free or esterified hydroxyl group or by a keto group, or A -3:20-dihydroxy-pregnadiene; pure alcohols which are epimeric in the 3-position or mixtures of these alcohols can be used.

According to the present process it is possible to obtain the hitherto unknown 21-unsubstituted A -3-oxo-20-hydroxy-pregnenes which contain in the ll-position a free or esterified hydroxyl group, a 9:11-double bond or a 9:11B-oxido group, and their A -3-ketals. In particular there may be mentioned A -3-oxo-1la:20-dihydroxy-pregnone and its ll-rnonoesters, A -3-oxo-1lliz20-dihydroxypregnene and its 11-monoesters, A -3-oxo-20-hydroxypregnadiene, A -3 -oxo-9: 11fi-oxido-20-hydroxy-pregnene and the corresponding A -3-ketals for example ethyleneketals, hemithioethyleneketals, propyleneketals and the like. The llp-hydroxyl group in the above compounds can be esterified with a lower fatty acid, for example formic acid, acetic acid, trifluoracetic acid, propionic acid and the like, the llu-hydroxyl group can also be esterified with an aromatic carboxylic acid, a benzoic acid or with a sulfonic acid, such as methanesulfonic acid, benzene-sulfonic acid or para-toluene-sulfonic acid.

The following examples illustrate the invention:

Example 1 2.5 grams of crude A -3:20-dihydroxy-1la-aeetoxypregnene are dissolved in 150 cc. of absolute benzene, 3.0 grams of aluminum tertiary butylate and 12 cc. of acetone are added and the Whole allowed to stand for 18 hours at 2022 C. The course of the oxidation can be followed by taking small test samples and determining the ultraviolet and infrared spectra. For example, after one hour a molar extinction of about 7000 is found at 241 m which corresponds to an oxidation of 47%. In the infrared spectrum the band of the A -3-ketone at about 6.00 1 is distinctly weaker than the band of the Ila-acetate up to about 5.79 1. After three hours the extinction at 241 me has risen to about 11,000 (approximately 75% of the maximum value) and the ketone band is only slightly weaker than the acetate band. After 6 hours an extinction of 12400 (about 82% of the maximum value) is found and the acetate and ketone bands have the same intensity. After 18 hours the maximum value of the extinction (about 15000) has been reached and the ketone band is stronger than the acetate band. The reaction mixture is diluted with benzene, washed with 2 N- hydrochloric acid and water, and the dried benzene solution is evaporated in a water-jet vaccum. The amorphous residue (2.65 grams) consists of A -3-oxo-11oc-acet0xy- ZQB-hydroxyregnene mixed with a slight quantity of the ZOOL-lSOlTlfiI'.

The above crude ketone is dissolved in 150 cc. of benzene and, after adding 30 cc. of ethylene glycol and 150 mg. of para-toluene-sulfonic acid, boiled under reflux for 16 hours using a water-separator. After cooling, the mixture is diluted with benzene, washed with sodium carbonate solution and water, and evaporated in a Waterjet vacuum. The crystalline residue is washed with a little cold methanol and 1.88 grams of pure A -3-ethylenedioxy-l la-acetoxy-20B-hydroxy-pregnene melting at 214- 219 C. are obtained. From the mother liquor about 200 mg. of somewhat less pure ketal precipitate.

The A -3:20-dihydroxy-lla-acetoxy-pregnene used as starting material is prepared as follows: 75 cc. of a 0.4 N-solution of lithium tri-tertiary butoxy-aluminum hymethylene chloride, the extracts washed with sodium bicarbonate solution and water, dried and evaporated to dryness. The residue is used directly for oxidation.

Example 2 A suspension of 3.0 grams of crude A -3:1lcz:2O-tri hydroxy-pregnene in 150 cc. of absolute benzene is stirred for 18 hours at 25 C. with the exclusion of moisture after the addition of 3.0 grams of aluminum tertiary butylate and 12 cc. of acetone; the mixture is then diluted with benzene, Washed with hydrochloric acid and water and the dried benzene solution evaporated. 3.01 grams of a solid, colorless crude product are obtained which on the basis of the ultraviolet spectrum (maximum at 241 m/L; e=13,200) consists of about of the mixture of the two A -3-oxo-l1a:20-dihydroxy-pregnenes epimeric in the 20-position. In the infrared spectrum the compound shows only the bands of the azfl-unsaturated ketone at 6.00 and 622 whereas no saturated ketone is detectable at 5.85 1. By crystallization from a mixture of methanol and ether pure A -3-oxo-1lot:205-dihydroxy-prcgnene is obtained which melts at 170-172" C; optical rotation [a] =+70 (in chloroform); ultraviolet maximum at 243 m 13,900).

By lretalization with ethylene glycol and paratoluene sulfonic acid in benzene as described in Example 1 19-3- cthylenedioxy 1101:20/3 dihydroxy-pregnene melting at 208-210 C. is obtained.

The 13 -3:11a:ZO-trihydroxy-pregnene used as starting material is prepared by reducing llu-hydroxy-progesterone with lithium aluminum hydride in tetrahydrofuran.

Example 3 2.70 grams of crude A -3:l7fi-dihydroxy-androstene are dissolved in 150 cc. of absolute benzene, 3.0 grams of aluminum tertiary butylate and 12 cc. of acetone are added and the whole allowed to stand for 18 hours at 25 C. The mixture is diluted with benzene, washed with hydrochloric acid and water, and the dried benzene solution evaporated in a water-jet vacuum. A crystalline residue is obtained which on the basis of the ultraviolet absorption spectrum contains about 90% of testosterone. By crystallization from aqueous methanol 2.39 grams of pure testosterone melting at 148150 C. are obtained.

Example 4 700 mg. of crude A -3:17fl-dihydroxy-androstene are dissolved in cc. of absolute benzene and after adding 1.0 gram of aluminum isopropylate and 300 mg. of anthraquinone the whole is stirred under oxygen at 35 C. In the course of 6 hours 42 cc. of oxygen are taken up. The reaction mixture is then diluted with benzene, Washed with hydrochloric acid and Water, and the dried benzene solution filtered through 10 grams of aluminum oxide and evaporated in a water-jet vacuum. The crystalline residue is taken up in ether, filtered from insoluble anthraquinone, the filtrate evaporated and crystallized from a mixture of ether and hexane. 610 mg. of pure testosterone melting at 147-150 C. are obtained.

Example 5 3.6 grams of crude A -3:2O-dihyclroxy-pregnadiene are dissolved in 150 cc. of absolute benzene, 3.0 grams of aluminum isopropylate and 12 ml. of acetone are added and the Whole allowed to stand for 20 hours at 30 C. After working up as described in Example 4, 3.74 grams a of an amorphous residue are obtained which in the ultra- 5 violet spectrum shows a strong absorption (e=l2,600) at 241 m;/.. In the infrared spectrum in the CO-region only the band of the unsaturated ketone at 6.00 is visible. The residue is crude A -3-oXo-20-hydroxy-pregnadiene.

35 cc. of ethylene glycol and 175 mg. of paratoluenesulfonic acid are added to the solution of the crude prodnot in 200 cc. of benzene, and the whole stirred under refiux for 10 hours at 130 C. bath temperature using a water-separator. After cooling, the mixture is diluted with benzene, washed with sodium bicarbonate solution and water, and the dried benzene solution evaporated in a water-jet vacuum. 4.29 grams of a crystalline residue are obtained from which pure A -3-ethylenedioxy-20- hydroxy-pregnadiene is isolated by crystallization from ether. It melts at 167-169 C., [a] =-33 (in chloroform); infrared spectrum: bands at 2.75p (hydroxyl); 9.18 ('kctal); further bands at 10.33 10.58;, 11.55,u and 1207 11.

Example 6 A solution of 2 grams of A -3IZO-dihYdIOXY-lloc-tOSYloxy-pregnene and 2.4 grams of aluminum tertiary butylate in 60 cc. of benzene and 9.6 cc. of acetone is stirred for 15 hours at 25 C. internal temperature in a weak current of nitrogen. The mixture is diluted with benzene, washed with dilute hydrochloric acid and water, and the aqueous solutions extracted with fresh benzene. After combining, drying and evaporating the organic solutions in a water-jet vacuum, A -3-oxo-11a-tosyloxy-20-hydroxypregnene is obtained in the form of a yellow oil. The infrared spectrum taken in a methylene chloride solution shows no band for a saturated ketone, but at 5.99s a strong band which is typical of A -3-ketones.

On ketalizing the above obtained 20-hydroxy-cornpound with a mixture of ethyleneglycol and benzene in the presence of para-toluenesulfonic acid there is obtained as main product in addition to a little A -3-ethylenedioxy-l1a-tosyloxy-20-hydroxy-pregnene which, when recrystallized from a mixture of methanol and water, melts at 138-139 C. with decomposition, A -3-ethylenedioxy-ZOfl-hydroxy-pregnadiene melting at 167l69 C. obtained by splitting off the tosylate group. This compound is identical with that described in Example 5.

The A 6:20-dihydroxy-1lot-tosyloxy-pregnene used as starting material is prepared as follows: A mixture of 5.6 grams of tertiary butyl alcohol and 1.4 cc. of tetrahydrofuran is added slowly to a mixture of 960 mg. of lithium aluminum hydride and 20 cc. of tetrahydrofuran with stirring and ice-cooling in a current of nitrogen. When the addition is complete, the whole is stirred for 30 minutes with ice-cooling, and 2 grams of A -3z20-dioxo-llatosyloxy-pregnene are then added while rinsing with 1.5 cc. of tetrahydro-furan. The temperature rises to 10 C. but falls again to C. shortly afterwards. 25 minutes later the mixture is diluted with benzene, 50 cc. of saturated Rochelle salt solution and cc. of saturated sodium chloride solution are added cautiously while cooling well, the solution layers are separated and the aqueous solution extracted once more with benzene. The organic solutions are washed with saturated Rochelle salt solution and water, dried and evaporated in a water-jet vacuum. The resulting crude A -3:2O-dihydroxy-11u-tosy1- oxy-pregnene displays no bands in the infrared spectrum between 5.5 1. and 6.0a and is used directly for the further steps of the process.

Example 7 2.5 grams of crude A -3:2O-dihydroxy-9:llfl-oxidopregnene are dissolved in 150 cc. of absolute benzene and, after adding 3.0 grams of aluminum isopropylate and 12 cc. of acetone, the whole is allowed to stand for 21 hours at 20-25 C. The mixture is then diluted with 100 cc. of benzene, the solution washed with cold 2 N-hydrochloric acid and water, the benzene solution dried and evaporated to dryness in a water-jet vacuum. The amorphorus residue consists of crude A -3-oxo-9:11fi-oxido- ZO-hydroxy-pregnene and exhibits in the ultraviolet spectrum a maximum at 240 mu (e=12,500).

The so-obtained crude product is dissolved in 150 cc. of benzene and, after the addition of a solution of 150 mg. of para-toluene-sulfonic acid in 30 cc. of ethyleneglycol, the whole is boiled under reflux for 6 hours using a water-separator. The mixture is then cooled, 50 cc. of saturated sodium bicarbonate solution are added with stirring, the whole diluted with cc. of benzene and the aqueous layer separated. The benzene solution is washed with water, dried and evaporated to dryness in a waterjet vacuum. There are obtained 2.62 grams of crude A -3-ethylenedioxy-9 1 1B oxido 20 hydroxy pregnene which is purified by chromatography on 75 grams of aluminum oxide.

The 3:20-diol used as starting material is prepared by reducing 2.5 grams of the known 9:11B-oxido-progesterone with lithium tritertiary butoxy aluminum hydride as described in Example 1.

Example 8 18.0 g. of crude A 3:20-dihydroxy-pregnene are dissolved in 300 ml. of absolute benzene, the solution treated with 48 ml. of acetone and 12 g. of aluminum isopropylate, and stirred for 18 hours at 30 C. It is then cooled in ice, treated dropwise with ml. of N-hydrochloric acid, the benzene layer is separated and w orked up as usual. There are obtained 18.1 g. of acr-ude product the IR spectrum of which exhibits between 5.5 and 6.5 only the bands of A -3-ketone at 6.01 and 6.22 1. It contains the 13 -3-oxo-20-hydroxy-pregnene as the main product.

The crude product is dissolved in 450 ml. of benzene, the solution mixed with 60 ml. of ethylene glycol and 420 ml. of para-toluene sulfonic acid, and the mixture boiled for 7 hours with the use of a water separator. The product is then worked up as described in Example 7. There are obtained 17.6 g. of a crystalline crude product from which there are obtained by recrystallization from a mixture of methylene chloride and alcohol 10.76 g. of A -3-ethylenedioxy-20fl-hydroxy-pregnene, which melts at 182-188" C. In addition to further quantities of the above 20,8-hydroxy compound, the mother liquor contains also the corresponding 20a-hydroxy compound.

The A -3:ZO-dihydroxy-pregnene used as starting material is obtained by reducing progesterone with lithium aluminum hydride in known manner.

What is claimed is:

1. Process for the selective oxidation of polyhydroxysteroids, wherein a polyhydroxy-steroid having at least two oxidizable carbinol groups, one of which has a double bond in the cup-position, is treated in an aromatic hydrocarbon with a member selected from the group consisting of aliphatic, alicyclic, araliphatic ketones and quinoues in the presence of a light metal alcoholate until absorption in ultraviolet light reaches a maximum between 230 and 260 mu.

2 Process as claimed in claim 1, wherein a A -3-hydroxy-steroid having at least one other free secondary hydroxyl group is used as starting material.

3. Process as claimed in claim 1, wherein a A -3:17dihydroxy-androstene is used as starting material.

4. Process as claimed in claim 1, wherein a A -3 :20-dihydroxy pregnene is used as starting material.

Fieser and Fieser Steroids (ReinholdNew York) June 25, 1959, pages 51 and 514 relied on.

Tetrahedron, vol. 6, No. 4 (Pergamon Press Ltd., Northern Ireland) June 1959, pp. 297 and 298. 

1. PROCESS FOR THE SELECTIVE OXIDATION OF POLYHYDROXYSTEROIDS, WHEREIN A POLYHYDROXY-STEROID HAVING AT LEAST TWO OXIDIZABLE CARBINOL GROUPS, ONE OF WHCH HAS A DOUBLE BOND IN THE A:B-POSITION, IS TREATED IN AN AROMATIC HYDROCARBON WITH A MEMBER SELECTED FROM THE GROUP CONSISTING OF ALIPHATIC, ALICYCLIC, ARALIPHATIC KETONES AND QUINONES IN THE PRESENCE OF A LIGHT METAL ALCOHOLATE UNTIL ABSORPTION IN ULTRAVILOLET LIGHT REACHES A MAXIMUM BETWEEN 230 AND 260 M$.
 4. PROCESS AS CLAIMED IN CLAIM 1, WHEREIN A $1-3:20-DIHYDROXY PREGNENE IS USED AS STARTING MATERIAL. 